The present invention relates generally to methods and compositions for locally inhibiting release of selected endogenous compounds, as might be particularly useful for inhibiting glutamate and aspartate release in central nervous system loci.
Therapeutic treatment of various central nervous system disorders has been difficult to achieve because of the failure to provide sustained drug delivery. For example, Thyrotropin-releasing hormone (TRH), an endogenous central nervous system tripeptide, as well as TRH analogs, have been shown to have effective but transient anticonvulsant effects in a variety of animal seizure models. Nevertheless, therapeutic treatment utilizing TRH has been previously unsuccessful in the treatment of epilepsy. In this regard, patients suffering intractable seizures benefited only briefly from repeated TRH and TRH analog treatment.
In particular, oral and injected delivery of TRH and other neural peptides as therapeutic agents have been inadequate because of poor penetration of the drug to the desired site. Contributing factors to the limited site-specific bioavailability of therapeutic agents in the central nervous system include rapid peripheral metabolism, poor intestinal absorption, insufficient blood brain barrier penetration, inability to use synthetic precursors, and untoward side effects. As a result, delivering the neural peptide systemically by way of general circulation and/or cerebrospinal fluid would undesirably distribute the neural peptide to nonspecific receptor sites, thereby causing untoward side effects both systemically as well as in the central nervous system.
In U.S. Pat. No. 5,360,610, Tice et al. disclose polymeric microspheres, having diameters ranging from 5 to 45 micrometers, as injectable, drug-delivery systems for delivering bioactive agents to sites within the central nervous system. However, the injectable microspheres described by Tice et al. are ill-suited to provide sustained drug delivery to central nervous system loci because the microspheres tend to disperse in extracellular cerebrospinal fluid (CSF) and are subject to nonspecific uptake and delivery to more distant sites in the brain by CSF through the circumventricular organs, glia and neurons themselves. Larger microspheres are also inadequate because of insufficient rate of release of the bioactive agent from the interior of the microsphere to the site to be treated.
Other prior art approaches have involved use of lipophilic analogs of known neuropeptides, or lipophilic organic look-a-like compounds at a high affinity neuropeptide binding site to mimic endogenous neuropeptide activity, in the hope of enhancing drug delivery to promote long-lasting effects. However, these approaches have been ineffective because of widespread distribution of the neuropeptide analog to non-targeted receptor sites resulting in untoward side effects. In addition, other previous attempts have included osmotic minipumps, attachment to liposomes and cerebroventricular infusion. These attempts have also been ineffective because osmotic minipumps need replenishment, can become clogged and are a source of potential cerebral infection. Liposome attachment results in widespread distribution including non-targeted receptor sites resulting in untoward side effects. Cerebroventricular infusion results in a short duration of action and widespread distribution to non-targeted receptor sites leading to side-effects.
From the foregoing, it will be appreciated that there exists a need in the art for site-specific drug delivery to central nervous system loci in which sustained release of the drug is achieved without dispersion of the drug from the original site of implantation which causes nonspecific uptake and delivery to non-targeted receptor sites. It will be appreciated that there also exists a need in the art for site-specific drug delivery in which the release of the drug can be sustained at a relatively constant rate if desired.
The aforesaid problems are solved, in accordance with the present invention, by compositions and methods for providing prolonged release of therapeutic agents in situ at a specific locus over time. Under the present invention, microstructures are provided to effectively deliver sustained and controllable release of therapeutic agents, such as neuroactive peptides and/or analogs, singly or in combination, by in situ stereotaxic implantation in specific central nervous system loci, including pathways, in order to treat known neurological disorders. The microstructures are most preferably in the shape of microdisks having upper and lower surfaces that are substantially parallel to each other and also having substantially circular perimeters that can be optimally adapted for delivery through a cannula, although the microdisks can include shapes in which the upper and lower surfaces are not substantially parallel, or the perimeters are not circular or even rounded, if desired.
The microstructures include a therapeutic agent which can, for example, serve as an agonist at particular receptor sites in, for example, neurons. The microstructures also include a carrier that is biodegradable at body temperature and is nontoxic. Examples of suitable carriers include polyanhydrides, particularly polymerized oleic acid dimers and sebacic acid polymers. A most preferred carrier is oleic acid dimer identified as poly(FAD-SA). It is to be noted that multiple microstructures can be implanted at a site in accordance with the present invention. In this regard, microstructures containing different drugs which can, for example, have synergistic effects, can be implanted together.
Advantageously, by providing stereotaxic in situ implantation of the long-release microstructures directly into the locus, including pathways, associated with, for example, a neurological disorder, the present invention eliminates barriers to drug delivery. Also, the microstructures of the present invention attenuate the possibility of untoward side effects through the stereotaxic implantation which confines the long-release microstructures to the locus of interest.
By way of example, microstructures of the present invention can be implanted to deliver TRH and/or its analogs to inhibit glutamate and aspartate, which are the primary and most abundant excitatory neurotransmitters used by nerve cells in the brain. By inhibiting glutamate and aspartate release, the microstructures of the present invention can be used to treat a number of neurodegenerative diseases of the central nervous system that are caused by excessive release of these transmitters, including, but not limited to, epilepsy, focal stroke, sclerosis, trauma, ischemia, Alzheimer""s dementia and motoneuron disease. Significantly, the sustained release provided by the microstructures of the present invention is essential in providing meaningful inhibition of glutamate and aspartate in order to treat the neurodegenerative disorders. For example, microstructures can be implanted at trauma sites in the spinal cord sustained by accident victims. By delivering TRH and/or TRH analogs to the traumatized spinal cord, the massive release of glutamate that typically accompanies swelling can be precluded thereby preventing excitotoxicity that otherwise kills cells due to the excessive glutamate release.
The present invention will be more fully understood upon reading the following detailed description of the preferred embodiments in conjunction with the accompanying drawings.